scholarly journals The Negative Effect of Protein Phosphatase Z1 Deletion on the Oxidative Stress Tolerance of Candida albicans Is Synergistic with Betamethasone Exposure

2021 ◽  
Vol 7 (7) ◽  
pp. 540
Author(s):  
Ágnes Jakab ◽  
Tamás Emri ◽  
Kinga Csillag ◽  
Anita Szabó ◽  
Fruzsina Nagy ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Candida Albicans ◽  
Protein Phosphatase ◽  
Combined Treatment ◽  
Specific Protein ◽  
Ergosterol Biosynthesis ◽  
Acid Oxidation ◽  
Menadione Sodium Bisulfite ◽  
Rnaseq Data ◽  
Negative Effect

The glucocorticoid betamethasone (BM) has potent anti-inflammatory and immunosuppressive effects; however, it increases the susceptibility of patients to superficial Candida infections. Previously we found that this disadvantageous side effect can be counteracted by menadione sodium bisulfite (MSB) induced oxidative stress treatment. The fungus specific protein phosphatase Z1 (CaPpz1) has a pivotal role in oxidative stress response of Candida albicans and was proposed as a potential antifungal drug target. The aim of this study was to investigate the combined effects of CaPPZ1 gene deletion and MSB treatment in BM pre-treated C. albicans cultures. We found that the combined treatment increased redox imbalance, enhanced the specific activities of antioxidant enzymes, and reduced the growth in cappz1 mutant (KO) strain. RNASeq data demonstrated that the presence of BM markedly elevated the number of differentially expressed genes in the MSB treated KO cultures. Accumulation of reactive oxygen species, increased iron content and fatty acid oxidation, as well as the inhibiting ergosterol biosynthesis and RNA metabolic processes explain, at least in part, the fungistatic effect caused by the combined stress exposure. We suggest that the synergism between MSB treatment and CaPpz1 inhibition could be considered in developing of a novel combinatorial antifungal strategy accompanying steroid therapy.

scholarly journals Deletion of the fungus specific protein phosphatase Z1 exaggerates the oxidative stress response in Candida albicans

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Krisztina Szabó ◽  
Ágnes Jakab ◽  
Szilárd Póliska ◽  
Katalin Petrényi ◽  
Katalin Kovács ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Candida Albicans ◽  
Stress Response ◽  
Protein Phosphatase ◽  
Transcript Level ◽  
Opportunistic Pathogen ◽  
Sublethal Concentration ◽  
Specific Protein ◽  
Oxidative Stress Response ◽  
Short Term Treatment

Abstract Background Candida albicans is an opportunistic pathogen which is responsible for widespread nosocomial infections. It encompasses a fungus specific serine/threonine protein phosphatase gene, CaPPZ1 that is involved in cation transport, cell wall integrity, oxidative stress response, morphological transition, and virulence according to the phenotypes of the cappz1 deletion mutant. Results We demonstrated that a short-term treatment with a sublethal concentration of tert-butyl hydroperoxide suppressed the growth of the fungal cells without affecting their viability, both in the cappz1 mutant and in the genetically matching QMY23 control strains. To reveal the gene expression changes behind the above observations we carried out a global transcriptome analysis. We used a pilot DNA microarray hybridization together with extensive RNA sequencing, and confirmed our results by quantitative RT-PCR. Novel functions of the CaPpz1 enzyme and oxidative stress mechanisms have been unraveled. The numbers of genes affected as well as the amplitudes of the transcript level changes indicated that the deletion of the phosphatase sensitized the response of C. albicans to oxidative stress conditions in important physiological functions like membrane transport, cell surface interactions, oxidation-reduction processes, translation and RNA metabolism. Conclusions We conclude that in the wild type C. albicans CaPPZ1 has a protective role against oxidative damage. We suggest that the specific inhibition of this phosphatase combined with mild oxidative treatment could be a feasible approach to topical antifungal therapy.

scholarly journals Synergistic Effect of Calcineurin Inhibitors and Fluconazole against Candida albicans Biofilms

2008 ◽  
Vol 52 (3) ◽  
pp. 1127-1132 ◽  
Author(s):  
Priya Uppuluri ◽  
Jeniel Nett ◽  
Joseph Heitman ◽  
David Andes
Keyword(s):  
Candida Albicans ◽  
Calcineurin Inhibitors ◽  
Drug Susceptibility ◽  
Specific Protein ◽  
Therapeutic Interventions ◽  
Ergosterol Biosynthesis ◽  
Drug Synergism ◽  
Planktonic Cells

ABSTRACT Calcineurin is a Ca2+-calmodulin-activated serine/threonine-specific protein phosphatase that governs multiple aspects of fungal physiology, including cation homeostasis, morphogenesis, antifungal drug susceptibility, and virulence. Growth of Candida albicans planktonic cells is sensitive to the calcineurin inhibitors FK506 and cyclosporine A (CsA) in combination with the azole antifungal fluconazole. This drug synergism is attributable to two effects: first, calcineurin inhibitors render fluconazole fungicidal rather than simply fungistatic, and second, membrane perturbation by azole inhibition of ergosterol biosynthesis increases intracellular calcineurin inhibitor concentrations. C. albicans cells in biofilms are up to 1,000-fold more resistant to fluconazole than planktonic cells. In both in vitro experiments and in an in vivo rat catheter model, C. albicans cells in biofilms were resistant to individually delivered fluconazole or calcineurin inhibitors but exquisitely sensitive to the combination of FK506-fluconazole or CsA-fluconazole. C. albicans strains lacking FKBP12 or expressing a dominant FK506-resistant calcineurin mutant subunit (Cnb1-1) formed biofilms that were resistant to FK506-fluconazole but susceptible to CsA-fluconazole, demonstrating that drug synergism is mediated via direct calcineurin inhibition. These findings reveal that calcineurin contributes to fluconazole resistance of biofilms and provide evidence that synergistic drug combinations may prove efficacious as novel therapeutic interventions to treat or prevent biofilms.

scholarly journals Genipin and Insulin Combined Treatment Improves Implant Osseointegration in Type 2 Diabetic Rats

2020 ◽  
Author(s):  
Jiajia Zhang ◽  
Ya-nan Wang ◽  
Tingting Jia ◽  
Haiyun Huang ◽  
Dongjiao Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Combined Treatment ◽  
Harmful Effect ◽  
Diabetic Rats ◽  
Control Group ◽  
Ampk Signaling ◽  
Glucose Levels ◽  
Negative Effect ◽  
Underlying Mechanisms

Abstract Background: Type 2 diabetes mellitus (T2DM) has a harmful effect on the stability and osseointegration of dental implants. T2DM induces mitochondrial damage by inhibiting AMPK signaling, resulting in oxidative stress and poor osteogenesis in the peri-implant bone area. Genipin is a major component of gardenia fruits with strong antioxidant, anti-inflammation, and anti-diabetic actions, and it also can activate mitochondrial quality control via the AMPK pathway. The purpose of this study was to investigate the effects of genipin and insulin treatment on implant osseointegration in T2DM rats and explore the underlying mechanisms. Methods: Streptozotocin-induced diabetic rats received implant surgery in their femurs, and were then assigned to five groups that were subjected to different treatments for three months: control group, T2DM group, insulin-treated T2DM group (10 IU/kg), genipin-treated T2DM group (50 mg/kg), and the genipin and insulin combination-treated T2DM group. Then, we regularly assessed the weight and glucose levels of the animals. Rats were euthanized at three months after the implantation procedure, and the femora were harvested for microscopic computerized tomography analysis, biomechanical tests, and different histomorphometric assessment. Results: The results indicated that the highest blood glucose and oxidative stress levels were measured for the T2DM group, resulting in the poorest osseointegration. The combination-treated T2DM group mitigated hyperglycemia and normalized, reactivated AMPK signaling, and alleviated oxidative stress as well as reversed the negative effect of osseointegration. There were beneficial changes observed in the T2DM-genipin and T2DM-insulin groups, but these were less in comparison to the combination treatment group. Conclusion: Our study suggests that treatment with genipin in combination with insulin could be an effective method for promoting implant osseointegration in T2DM rats, which may be related to AMPK signaling.

scholarly journals Mitochondria InfluenceCDR1Efflux Pump Activity, Hog1-Mediated Oxidative Stress Pathway, Iron Homeostasis, and Ergosterol Levels in Candida albicans

2013 ◽  
Vol 57 (11) ◽  
pp. 5580-5599 ◽  
Author(s):  
Edwina Thomas ◽  
Elvira Roman ◽  
Steven Claypool ◽  
Nikhat Manzoor ◽  
Jesús Pla ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Candida Albicans ◽  
Cellular Response ◽  
Iron Homeostasis ◽  
Sufficient Conditions ◽  
Ergosterol Biosynthesis ◽  
Biosynthesis Pathway ◽  
Content Type ◽  
Iron Assimilation ◽  
Increased Susceptibility

ABSTRACTMitochondrial dysfunction inCandida albicansis known to be associated with drug susceptibility, cell wall integrity, phospholipid homeostasis, and virulence. In this study, we deletedCaFZO1, a key component required during biogenesis of functional mitochondria. Cells withFZO1deleted displayed fragmented mitochondria, mitochondrial genome loss, and reduced mitochondrial membrane potential and were rendered sensitive to azoles and peroxide. In order to understand the cellular response to dysfunctional mitochondria, genome-wide expression profiling offzo1Δ/Δ cells was performed. Our results show that the increased susceptibility to azoles was likely due to reduced efflux activity ofCDRefflux pumps, caused by the missorting of Cdr1p into the vacuole. In addition,fzo1Δ/Δ cells showed upregulation of genes involved in iron assimilation, in iron-sufficient conditions, characteristic of iron-starved cells. One of the consequent effects was downregulation of genes of the ergosterol biosynthesis pathway with a commensurate decrease in cellular ergosterol levels. We therefore connect deregulated iron metabolism to ergosterol biosynthesis pathway in response to dysfunctional mitochondria. Impaired activation of the Hog1 pathway in the mutant was the basis for increased susceptibility to peroxide and increase in reactive oxygen species, indicating the importance of functional mitochondria in controlling Hog1-mediated oxidative stress response. Mitochondrial phospholipid levels were also altered as indicated by an increase in phosphatidylserine and phosphatidylethanolamine and decrease in phosphatidylcholine infzo1Δ/Δ cells. Collectively, these findings reinforce the connection between functional mitochondria and azole tolerance, oxidant-mediated stress, and iron homeostasis inC. albicans.

scholarly journals Genipin and insulin combined treatment improves implant osseointegration in type 2 diabetic rats

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jiajia Zhang ◽  
Ya-nan Wang ◽  
Tingting Jia ◽  
Haiyun Huang ◽  
Dongjiao Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Combined Treatment ◽  
Harmful Effect ◽  
Diabetic Rats ◽  
Control Group ◽  
Ampk Signaling ◽  
Glucose Levels ◽  
Negative Effect ◽  
Underlying Mechanisms

Abstract Background Type 2 diabetes mellitus (T2DM) has a harmful effect on the stability and osseointegration of dental implants. T2DM induces mitochondrial damage by inhibiting AMPK signaling, resulting in oxidative stress and poor osteogenesis in the peri-implant bone area. Genipin is a major component of gardenia fruits with strong antioxidant, anti-inflammation, and antidiabetic actions, and it also can activate mitochondrial quality control via the AMPK pathway. The purpose of this study was to investigate the effects of genipin and insulin treatment on implant osseointegration in T2DM rats and explore the underlying mechanisms. Methods Streptozotocin-induced diabetic rats received implant surgery in their femurs and were then assigned to five groups that were subjected to different treatments for three months: control group, T2DM group, insulin-treated T2DM group (10 IU/kg), genipin-treated T2DM group (50 mg/kg), and the genipin and insulin combination-treated T2DM group. Then, we regularly assessed the weight and glucose levels of the animals. Rats were euthanized at 3 months after the implantation procedure, and the femora were harvested for microscopic computerized tomography analysis, biomechanical tests, and different histomorphometric assessment. Results The results indicated that the highest blood glucose and oxidative stress levels were measured for the T2DM group, resulting in the poorest osseointegration. The combination-treated T2DM group mitigated hyperglycemia and normalized, reactivated AMPK signaling, and alleviated oxidative stress as well as reversed the negative effect of osseointegration. There were beneficial changes observed in the T2DM-genipin and T2DM-insulin groups, but these were less in comparison to the combination treatment group. Conclusion Our study suggests that treatment with genipin in combination with insulin could be an effective method for promoting implant osseointegration in T2DM rats, which may be related to AMPK signaling.

Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

2020 ◽  
Vol 21 (6) ◽  
pp. 599-609 ◽  
Author(s):  
Longxin Qiu ◽  
Chang Guo
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Aldose Reductase ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

The mechanisms involved in obesity-induced male infertility

2020 ◽  
Vol 16 ◽  
Author(s):  
Hamed Heydari ◽  
Rafighe Ghiasi ◽  
Saber Ghaderpour ◽  
Rana Keyhanmanesh
Keyword(s):  
Oxidative Stress ◽  
Metabolic Disease ◽  
Male Infertility ◽  
Male Fertility ◽  
Reproductive Function ◽  
Disease Development ◽  
Significant Evidence ◽  
Male Reproductive Function ◽  
Negative Effect ◽  
And Oxidative Stress

Introduction: Obesity resulted by imbalance between the intake of energy and energy consumption can lead to growth and metabolic disease development in people. Both in obese men and animal models, several studies indicate that obesity leads to male infertility. Objective: This review has discussed some mechanisms involved in obesity-induced male infertility. Method: Online documents were searched through Science Direct, Pubmed, Scopus, and Google Scholar websites dating from 1959 to recognize studies on obesity, kisspeptin, leptin, and infertility. Results: Obesity induced elevated inflammatory cytokines and oxidative stress can affect male reproductive functions including spermatogenesis disorders, reduced male fertility power and hormones involved in hypothalamus-pituitarygonadal axis. Conclusion: There is significant evidence that obesity resulted in male infertility. obesity has negative effect on male reproductive function via several mechanisms such as inflammation and oxidative stress.

Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

2019 ◽  
Vol 15 (6) ◽  
pp. 648-658 ◽  
Author(s):  
Manzoor Ahmad Malik ◽  
Shabir Ahmad Lone ◽  
Parveez Gull ◽  
Ovas Ahmad Dar ◽  
Mohmmad Younus Wani ◽  
...  
Keyword(s):  
Schiff Base ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Infections ◽  
Total Sterol ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Ergosterol Biosynthesis ◽  
Dependent Manner ◽  
Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

scholarly journals Identification of a serine/threonine-specific protein phosphatase from the archaebacterium Sulfolobus solfataricus.

1993 ◽  
Vol 268 (9) ◽  
pp. 6505-6510
Author(s):  
P.J. Kennelly ◽  
K.A. Oxenrider ◽  
J. Leng ◽  
J.S. Cantwell ◽  
N. Zhao
Keyword(s):  
Protein Phosphatase ◽  
Sulfolobus Solfataricus ◽  
Specific Protein
Sign in / Sign up

Export Citation Format

Share Document